The levels of evidence (class I-IV) supporting the recommendations and levels of recommendation (A-C, Good Practice Point) are defined at the end of the "Major Recommendations" field.
Clinical Diagnosis: Medical History, Laboratory, Neurological, and Physical Examination
Clinical history should be supplemented by an informant (Good Practice Point) (Hort et al., 2010; American Psychiatric Association (APA), Task Force on DSM-IV, 2000; International Statistical Classification of Diseases and Related Health Problems 10th Revision Version [ISCD] for 2007; Diagnostic Statistical Manual DSM 5 [DSM5], 2012). A neurological and general physical examination should be performed in all patients with dementia (Good Practice Point) (Hort et al., 2010; APA Task Force on DSM-IV, 2000; ISCD, 2007; DSM5, 2012; Rossor et al., 2010). Routine blood tests are useful in excluding co-morbidities (Good Practice Point) (Knopman et al., 2001).
Assessment of Cognitive Functions, Screening Tests, and Assessment of Specific Cognitive Domains
Cognitive assessment is central to diagnosis and management of dementias and should be performed in all patients (Level A) (Knopman et al., 2001). Screening tests are available of good accuracy in the general diagnosis of dementia or have been proposed specifically for the differential diagnosis between the different forms of dementia (Good Practice Point) (Knopman et al., 2001). Neuropsychological assessment should be performed in all patients in the early stages of the disease (Level B) when the cognitive impairment reflects the disruption of specific brain structures (Hort et al., 2010; APA Task Force on DSM-IV, 2000; ISCD, 2007; DSM5, 2012; Braak & Braak, 1991). The neuropsychological assessment should include a global cognitive measure, and in addition, more detailed testing of the main cognitive domains including memory, executive functions, and instrumental functions (Level C) (Knopman et al., 2001).
Assessment of Behavioural and Psychological Symptoms of Dementia (BPSD)
Assessment of BPSD is essential for both diagnosis and management and should be performed in each patient (Good Practice Point) (Aalten et al., 2008). Information is gathered from an informant using an appropriate rating scale (Good Practice Point) (Conn & Thorpe, 2007). Although specific BPSD form the core or supportive features of some non-Alzheimer's disease dementias, co-morbidity should always be considered as a possible cause (Good Practice Point) (Gorno-Tempini et al., 2011; Rascovsky et al., 2011; McKeith, 2006; Emre et al., 2007).
Assessment of Activities of Daily Living (ADL)
ADL and Instrumental ADL (IADL) impairment because of cognitive decline is an essential part of the diagnostic criteria for dementia and should be assessed in the diagnostic evaluation (Good Practice Point) (Galasko et al., 1997; Pfeffer et al., 1982; DeJong, Osterlund, & Roy, 1989; Lawton & Brody, 1969; Gelinas et al., 1999; Gleichgerrcht et al., 2009; Mioshi & Hodges, 2009). A semi-structured interview from the caregiver is the most practical way to obtain relevant information, and various validated scales translated into different languages are available (Good Practice Point) (Galasko et al., 1997; Pfeffer et al., 1982; DeJong, Osterlund, & Roy, 1989; Lawton & Brody, 1969; Gelinas et al., 1999; Gleichgerrcht et al., 2009; Mioshi & Hodges, 2009).
Assessment of Co-morbidity
Assessment of co-morbidity is important in demented patients, both at the time of diagnosis and throughout the course of the illness (Good Practice Point) (Fu et al., 2004) and should always be considered as a possible cause of BPSD (Good Practice Point) (Meier & Lemcke, 2010). Blood levels of folate, vitamin B12, thyroid-stimulating hormone, calcium, glucose, complete blood cell count, renal and liver function tests should be evaluated at the time of diagnosis and serological tests for syphilis, Borrelia, and human immunodeficiency virus (HIV) might also be needed in cases with atypical presentation or clinical features suggestive of these disorders (Good Practice Point) (Knopman et al., 2001).
Structural imaging should be used in the evaluation of every patient affected by dementia (Level A) (Clarfield, 2003). Computed tomography (CT) and standard magnetic resonance imaging (MRI) are used to exclude secondary causes for dementia such as tumour, inflammatory disease, including abscess or normal-pressure hydrocephalus (Level A) (Clarfield, 2003). It is particularly difficult to attribute clinical significance to the evidence of cerebrovascular disease in patients with cognitive impairment. At the current state of knowledge, demonstration of cerebrovascular disease on imaging is used to support the diagnosis (Good Practice Point) (Van Straaten et al., 2003; Gold et al., 2002). Atrophy distribution is useful in the differential diagnosis of frontotemporal lobar degeneration (FTLD) compared with Alzheimer's disease (AD) and of the subtypes of FTLD (Level C) (Kipps et al., 2009; Galton et al., 2001; Kipps et al., 2007). No established structural MRI pattern is characteristic for dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) (Good Practice Point) (Burton et al., 2004). MRI is used to distinguish progressive supranuclear palsy (PSP) from DLB, being midbrain and the superior cerebellar peduncles atrophic in PSP (Good Practice Point) (Burton et al., 2004). The pronounced atrophy of the caudate nucleus and putamen is characteristic, and the so-called bicaudate ratio doubles of Huntington's disease (HD) (Level B) (Kuehn, 2011; Quattrone et al., 2008). MRI showing diffusion-weighted imaging (DWI) cortical rims, striatal and/or thalamic hyperintensities is useful for the diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) (Level A) (Zerr et al., 2009; Young et al., 2005). The MRI pulvinar sign, that is, symmetrical fluid attenuated inversion recovery (FLAIR) hyperintensity of the posterior thalamus, has high diagnostic utility for variant CJD (Level B) (Zeidler et al., 2000). Diffusion-tensor imaging (DTI) MRI distinguishes FTLD from AD and controls (and AD from controls) (Level B) (Avants et al., 2010; Whitwell et al., 2010). Measuring flow void on MRI can increase confidence on neuropsychiatric inventory (NPI) diagnosis and on decision about shunt placement (Good Practice Point) (Palm et al., 2006). Hyperintense signal abnormality on T2-weighted images within medial temporal lobe structures such as the hippocampi and amygdalae and, on occasion, the hypothalamus are commonly seen in limbic encephalitis (Level C).
Functional Imaging Modalities
DTI MRI distinguishes frontotemporal dementia (FTD) from AD and controls (and AD from controls) (Level B) (Avants et al., 2010; Whitwell et al., 2010). DTI MRI shows the distinct patterns of diffusivity changes, in parkinsonistic disorders (PDD, DLB, progressive supranuclear palsy [PSP], corticobasal syndrome [CBS]) (Level C) (Whitwell et al., 2010). Single-photon emission computed tomography (SPECT) perfusion and MRI morphometric imaging are useful to distinguish DLB, CBS, CJD from AD (Good Practice Point) (Kantarci et al., 2010; Erbetta et al., 2009; Ukisu et al., 2005). SPECT pre-synaptic dopamine transporter imaging is useful to distinguish DLB from non-DLB dementias (Level B) (Goto et al., 2010; O'Brien et al., 2009). SPECT and positron emission tomography (PET) perfusion and metabolic techniques are highly useful in FTLD diagnosis (Mendez et al., 2007; Rabinovici et al., 2008; Josephs et al., 2010) (Level C).
EEG is recommended in rapid dementia and differential diagnosis when CJD or transient epileptic amnesia is suspected (Level B) (Jelic & Kowalski, 2009; Liedorp et al., 2009; Wieser, Schindler, & Zumsteg, 2006). There is not enough evidence to consider resting EEG for the initial assessment of all dementia patients.
Cerebrospinal Fluid (CSF) Analysis
Routine CSF analysis may help to rule out or rule in certain infectious causes (Good Practice Point) (Jesse et al., 2011). CSF abeta 1-42/tau/p-tau assessment helps to differentiate AD (Level B) (Spies et al., 2010). Assessment of CSF total tau and 14-3-3 protein is recommended in rapidly progressive dementia when sporadic CJD (sCJD) is suspected (Good Practice Point) (Van Harten et al., 2011; Sanchez-Juan et al., 2006).
No studies have addressed the value of genetic counselling for patients with dementia or their families when autosomal-dominant disease is suspected. Because the genetics of dementing illnesses is a very young field, expertise in genetic counselling for the dementias of the elderly is likely to be found only in specialized dementia research centres (Good Practice Point) (Goldman et al., 2011; Prusiner & Hsiao, 1994; "Guidelines for the molecular genetics," 1994). Screening for known pathogenic mutations can be undertaken in patients with appropriate phenotype or a family history of an autosomal-dominant dementia. This should only be undertaken in specialist centres with appropriate counselling of the patient and family caregivers, and with consent (Good Practice Point). Pre-symptomatic testing may be performed in adults where there is a clear family history, and when there is a known mutation in an affected individual to ensure that a negative result is clinically significant. It is recommended that the Huntington's disease protocol is followed (Good Practice Point).
Biopsy and Other Investigations
Brain and other specific tissue biopsies can provide a diagnosis in rare or rapidly progressing dementias, but should only be carried out in specialist centres in carefully selected cases (Good Practice Point) (Schott et al., 2010; Warren et al., 2005).
Management of the Dementias
Primary and Secondary Prevention
No treatments, nor lifestyle, have demonstrated the efficacy for preventing or delaying the development of the different types of dementias until now.
Treatment of Cognitive Deficits in Non-Alzheimer Dementias
Use of cholinesterase inhibitors (ChEIs), memantine or selective serotonin reuptake inhibitors (SSRIs) in any of the FTLD subtypes is possibly ineffective for cognitive improvement (Level C) (Bei et al., 2010; Lebert et al., 2004). Dopaminergic replacement with bromocriptine in progressive aphasias is probably ineffective (Good Practice Point) (Reed et al., 2004). Given the insufficient classes II and III evidence and the evidence being largely based on class IV, the use of ChEIs and memantine in FTLD cannot be recommended. There is little class III evidence in support of rivastigmine and memantine (Bei et al., 2010; Lebert et al., 2004). There is no independent evidence for recommending any therapeutic intervention for CBS (Litvan et al., 2001; Zerr, 2009). Rivastigmine is the approved ChEI for the treatment of PDD with class I evidence. PDD diagnosis warrants the use of rivastigmine (Good Practice Point) (Maidment, Fox, & Boustani, 2006). Parallels with PDD in terms of clinical picture and disease mechanisms suggest that rivastigmine is possibly effective in DLB (GPP). The evidence for the efficacy of galantamine is insufficient for both PDD and DLB. Memantine is probably effective for both PDD and DLB (Level B) as there were consistently significant improvements in global measures, but not in cognitive measures in two class II studies (Aarsland et al., 2009; Emre et al., 2010). There is insufficient evidence for recommending any specific agent in the treatment of human prion diseases. Surgical treatment can be considered in normal pressure hydrocephalus (NPH) (Level C), and risk to benefit ratio must be individualized for each patient (Marmarou et al., 2005; Esmonde & Cooke, 2002). There is insufficient evidence for recommending any of non-pharmacological treatments.
Treatments of BPSD
Antipsychotic medications, conventional and atypical agents, may be utilized in clinical practice for aggression, psychosis, and agitation as well as SSRIs for mood and behavioural disorders (Good Practice Point) (Ballard & Corbett, 2010); however, there is little evidence to guide practice.
Counselling and Support for Caregivers
A dementia diagnosis mandates an inquiry to the community for available public health care support programs (Good Practice Point) (Ballard & Corbett, 2010). Counselling and case/care management amongst caring family members have positive effects on burden and satisfaction for caregivers of people with dementia (Good Practice Point).
Decision-Making and Participating in Research
Research involving persons affected by dementia needs to adopt special precautions, and there is consensus over the fact that adults who lack capacity should be supported by proxy consent when involved in research (Good Practice Point) (Gainotti et al., 2010).
Assessment of driving ability should be made after diagnosis with particular attention paid to visuo-spatial, visuo-perceptual, and executive abilities (Good Practice Point). Advice either to allow driving, but to review after an interval, to cease driving, or to refer for retesting should be given (Good Practice Point) (Adler & Rottunda, 2011).
Evidence Classification Scheme for a Diagnostic Measure
Class I: A prospective study in a broad spectrum of persons with the suspected condition, using a 'gold standard' for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy
Class II: A prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by 'gold standard') compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy
Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation
Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls)
Evidence Classification Scheme for a Therapeutic Intervention
Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:
- Randomization concealment
- Primary outcome(s) is/are clearly defined
- Exclusion/inclusion criteria are clearly defined
- Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
- Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment
Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion
Rating of Recommendations for a Diagnostic Measure
Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (established as possibly useful/predictive or not useful/predictive) requires at least two convincing class III studies.
Good Practice Points (GPP) Where there was a lack of evidence, but clear consensus, good practice points are provided.
Rating of Recommendations for a Therapeutic Intervention
Level A rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (possibly effective, ineffective, or harmful) requires at least two convincing class III studies.
Good Practice Points (GPP) Where there was a lack of evidence, but clear consensus, good practice points are provided.